SK19499A3 - Process for producing drospirenone (6beta,7beta;15beta,16beta- -dimethylene-3-oxo-17'alpha'-pregn-4-en-21,17-carbolactone), as well as 7'alpha'-(3-hydroxy-1-propyl)-6beta,7beta;15beta,16beta- -dimethylene-5beta-androstane-3beta,5,17beta-triol and 6beta,7beta;15beta,16beta-dimethylene-5beta-hydroxy-5-oxo- -17'alpha'-androstane-21,17-carbolactone - Google Patents
Process for producing drospirenone (6beta,7beta;15beta,16beta- -dimethylene-3-oxo-17'alpha'-pregn-4-en-21,17-carbolactone), as well as 7'alpha'-(3-hydroxy-1-propyl)-6beta,7beta;15beta,16beta- -dimethylene-5beta-androstane-3beta,5,17beta-triol and 6beta,7beta;15beta,16beta-dimethylene-5beta-hydroxy-5-oxo- -17'alpha'-androstane-21,17-carbolactone Download PDFInfo
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- SK19499A3 SK19499A3 SK194-99A SK19499A SK19499A3 SK 19499 A3 SK19499 A3 SK 19499A3 SK 19499 A SK19499 A SK 19499A SK 19499 A3 SK19499 A3 SK 19499A3
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- Prior art keywords
- dimethylene
- hydroxy
- alpha
- androstane
- beta
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- METQSPRSQINEEU-UHFFFAOYSA-N dihydrospirorenone Natural products CC12CCC(C3(CCC(=O)C=C3C3CC33)C)C3C1C1CC1C21CCC(=O)O1 METQSPRSQINEEU-UHFFFAOYSA-N 0.000 title claims abstract description 24
- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 title claims abstract description 19
- 229960004845 drospirenone Drugs 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims description 18
- 230000008569 process Effects 0.000 title claims description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 150000003303 ruthenium Chemical class 0.000 claims abstract description 3
- -1 3-hydroxy-1-propyl Chemical group 0.000 claims description 16
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 101000605827 Homo sapiens Pinin Proteins 0.000 claims description 6
- 102100038374 Pinin Human genes 0.000 claims description 6
- METQSPRSQINEEU-OLKMEILKSA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3C3C4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-OLKMEILKSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 claims 2
- 239000000543 intermediate Substances 0.000 abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001845 chromium compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910000423 chromium oxide Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WHFKIZXBVFEJGA-UHFFFAOYSA-L dihydroxy(dioxo)chromium;pyridine Chemical compound O[Cr](O)(=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 WHFKIZXBVFEJGA-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical class C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VVNXEADCOVSAER-UHFFFAOYSA-N lithium sodium Chemical compound [Li].[Na] VVNXEADCOVSAER-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
- C07J53/004—3 membered carbocyclic rings
- C07J53/007—3 membered carbocyclic rings in position 6-7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
- C07J53/004—3 membered carbocyclic rings
- C07J53/008—3 membered carbocyclic rings in position 15/16
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyrane Compounds (AREA)
- Fats And Perfumes (AREA)
- Polyesters Or Polycarbonates (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
Oblasť technikyTechnical field
Vynález sa týka spôsobu výroby drospirenónu (6β,7β,'15β,16β-€1ΪΓηθΙνΙέη3-oxo-17a-pregn-4-én-21,17-karbolaktón, DRSP), ako aj 7a-(3-hydroxy-1propyl)-6p,7p;15p,16p-dimetylén-5p-androstán-3p,5,17p-triolu (ZK 92836) a 6β,7β; 15β, 16p-dimetylén-5p-hydroxy-3-oxo-17a-androstán-21,17-karbolaktónu (90965) ako medziproduktov pre túto výrobu.The present invention relates to a process for the production of drospirenone (6β, 7β, 15β, 16β-, 1β-α-3-oxo-17α-pregn-4-ene-21,17-carbolactone, DRSP) as well as 7α- (3-hydroxy-1-propyl) - 6β, 7β; 15β, 16β-dimethylene-5β-androstane-3β, 5,17β-triol (ZK 92836) and 6β, 7β; 15β, 16β-dimethylene-5β-hydroxy-3-oxo-17α-androstane-21,17-carbolactone (90965) as intermediates for this production.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Drospirenón (6p,7p;15p,16p-dimetylén-3-oxo-17a-pregn-4-én-21,17karbolaktón, DRSP, INN) je ako steroidná látka už dlhú dobu známy (DE 26 52 761 C2 a DE 30 22 377 A1) a jeho výroba v posledných štyroch krokoch prebieha jednonádobovým postupom, pri ktorom sa po hydrogenácii dimetylénpropinolu ZK 34506 neizolujú žiadne priebežné medzistupne dimetylénpropanol a δ-β-ΟΗ-DRSP (viď. nasledujúcu reakčnú schému).Drospirenone (6β, 7β; 15β, 16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17 carbolactone, DRSP, INN) has been known for a long time as a steroid (DE 26 52 761 C2 and DE 30 22 377 A1) and its production in the last four steps is carried out in a one-pot procedure in which no intermediate intermediate dimethylene propanol and δ-β-ΟΗ-DRSP are isolated after the hydrogenation of dimethylene propinol ZK 34506 (see the following reaction scheme).
31168/H31168 / H
ZK 3~cC6ZK 3 ~ cC6
ττ
FDC/DMFFDC / DMF
Dimetylénpropinol ZK 34506 sa hydrogenuje v tetrahydrofuráne vodíkom na paládiu na uhlí na dimetylénpropanol ZK 92836. Takto získaný hydrogenačný roztok, ktorý obsahuje ako hlavný produkt dimetylénpropanol ZK 92836 a kolísavé podiely laktolu, sa bez izolácie a medzispracovania nechá reagovať na drospirenón ZK 30595 (DRSP).Dimethylene propinol ZK 34506 is hydrogenated in tetrahydrofuran with hydrogen on palladium on carbon to dimethylene propanol ZK 92836. The thus obtained hydrogenation solution, which contains dimethylene propanol ZK 92836 as the main product and fluctuating amounts of lactol, is reacted without distillation and treatment (DR95).
Pri tom sa najprv u skutoční výmena rozpúšťadla tetrahydrofuránu za dimetylformamid a potom sa propanol pri teplote 40 °C oxiduje prebytkom 3,7 ekvivalentov pyridíniumchromátu (PDC) na zmes DRSP a δ-β-ΟΗ-DRSP. 5-βOH-funkcia v oxidačnom produkte je nestabilná voči kyselinám, Lewisovým kyselinám a bázickým zlúčeninám pri zvýšených teplotách, pretože vo všetkých pripaďoch sa s vytvorením delta-4,5-nenasýteného ketónu v drospirenóne získa termodynamicky stabilný produkt. Eliminácia β-ΟΗ-funkcie v δ-β-ΟΗ-DRSP prebieha k termodynamicky stabilnému drospirenónu a nemohla by byť potlačená.In this case, the tetrahydrofuran solvent is first exchanged for dimethylformamide and then the propanol is oxidized at 40 ° C with an excess of 3.7 equivalents of pyridinium chromate (PDC) to a mixture of DRSP and δ-β-ΟΗ-DRSP. The 5-βOH function in the oxidation product is unstable to acids, Lewis acids and basic compounds at elevated temperatures, since in all cases the formation of a delta-4,5-unsaturated ketone in drospirenone yields a thermodynamically stable product. Elimination of β-ΟΗ-function in δ-β-ΟΗ-DRSP proceeds to thermodynamically stable drospirenone and could not be suppressed.
31168/H31168 / H
Zmes obsahuje spravidla premenlivé podiely oboch komponentov, pričom ϋ-β-ΟΗ-DRSP sa všeobecne vyskytuje ako hlavný komponent v pomere 2 až 3 : 1. V poslednom stupni jednonádobového postupu sa dvojkomponentná zmes prevedie prídavkom polokoncentrovanej kyseliny chlorovodíkovej na surový DRSP.As a rule, the mixture contains varying proportions of the two components, with ϋ-β-ΟΗ-DRSP generally occurring as the main component in a ratio of 2 to 3: 1. In the final step of the one-pot process, the two-component mixture is converted to crude DRSP by addition.
V nasledujúcej tabuľke sú zhrnuté výsledky posledných štyroch pracovných krokov.The results of the last four steps are summarized in the following table.
Tabuľkatable
V priemere všetkých pracovných krokov, keď sa vychádza z dimetylénpropinolu, sa dosiahne teoretický výťažok 56 % pri čistote podľa HPLC 98,9 %.On average, all the steps, starting from dimethylenepropinol, achieve a theoretical yield of 56% with an HPLC purity of 98.9%.
Úlohou predloženého vynálezu je vypracovanie nového spôsobu výroby drospirenónu, ktorý by bol selektívnejší a jednoduchší pri uskutočňovaní, ako spôsob podľa stavu techniky, a ktorý by bol okrem toho ekologickejší (ušetrenie oxidácie oxidom chrómovým).SUMMARY OF THE INVENTION It is an object of the present invention to provide a new process for the production of drospirenone that is more selective and simpler to carry out than the prior art process and which is more environmentally friendly (saving chromium oxide oxidation).
Podstata vynálezuSUMMARY OF THE INVENTION
Predmetom predloženého vynálezu je spôsob výroby drospirenónu (6p,7p;15p,16p-dimetylén-3-oxo-17a-pregn-4-én-21,17-karbolaktón, DRSP)SUMMARY OF THE INVENTION The present invention provides a process for the preparation of drospirenone (6β, 7β; 15β, 16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone, DRSP)
31168/H31168 / H
spočíva v tom, že sa uskutočňuje katalytická hydrogenácia 7a-(3-hydroxy-1propinyl)-6p,7p;15p,16p-dimetylén-5p-androstán-3p,5,17p-triolu (ZK 34506)consists of catalytic hydrogenation of 7α- (3-hydroxy-1-propynyl) -6β, 7β; 15β, 16β-dimethylene-5β-androstane-3β, 5,17β-triol (ZK 34506)
na 7a-(3-hydroxy-1-propyl)-6p>7p;15p,163-dimetylén-5p-androstán-3p,5,17ptriol (ZK 92836)to 7α- (3-hydroxy-1-propyl) -6β > 7β; 15β, 163-dimethylene-5β-androstane-3β, 5.17-triol (ZK 92836)
ZK 92S36 ďalej oxidácia za prítomnosti komerčne dostupných solí ruténia, ako je RuCI3, RuO2, KRuO4 a K2RuO4, výhodne však za prítomnosti katalytického množstva chloridu ruténitého (1 % mol) pomocou doterajších jednoduchých oxidačných činidiel, ako je terc.-butylhydroperoxid, N-metylmorfolín-N-oxid, M2S2O8 (M =Furthermore, ZK 92S36 oxidation in the presence of commercially available ruthenium salts such as RuCl 3 , RuO 2 , KRuO 4 and K 2 RuO 4 , but preferably in the presence of a catalytic amount of ruthenium chloride (1 mol%) by prior simple oxidizing agents such as tert. -butyl hydroperoxide, N-methylmorpholine-N-oxide, M 2 S 2 O 8 (M =
31168/H31168 / H
Na, K) a MXOy (M = Li, Na, K ; X = B, Cl ; y = 1 až 4), výhodne však 1 až 3 ekvivalentov NaBrO31 v rozpúšťadlách, ako je acetonitril, chloroform, metylénchlorid, tetrachlórmetán, voda, tetrahydrofurán, terc.-butanol, etylester kyseliny octovej alebo ich zmesi, výhodne však v zmesi acetonitril-voda v pomere 1 : 1, na 6p,7p;15p,16p-dimetylén-5p-hydroxy-3-oxo-17a-androstán21,17-karbolaktón (ZK 90965)Na, K) and MXO γ (M = Li, Na, K; X = B, Cl; γ = 1 to 4), but preferably 1 to 3 equivalents of NaBrO 31 in solvents such as acetonitrile, chloroform, methylene chloride, carbon tetrachloride, water, tetrahydrofuran, tert-butanol, ethyl acetate or mixtures thereof, preferably 1: 1 acetonitrile-water, to 6p, 7p; 15p, 16p-dimethylene-5p-hydroxy-3-oxo-17a-; androstane21,17-carbolactone (ZK 90965)
OABOUT
OH a nakoniec odštiepenie vody.OH and finally the cleavage of water.
Podľa predloženého vynálezu sa uskutočňuje ako kľúčová reakcia ruténiom katalyzovaná oxidácia dimetylénpropanolu ZK 92836 na 5-β-ΟΗDRSP ZK 90965 a nasledujúca eliminácia vody na drospirenón ZK 30595 dvojstupňovým postupom.According to the present invention, as a key reaction, ruthenium catalyzed oxidation of dimethylene propanol ZK 92836 to 5-β-βDRSP ZK 90965 followed by elimination of water to drospirenone ZK 30595 by a two-step process.
Analogicky ako u spôsobov, známych zo stavu techniky, sa pri spôsobe podľa predloženého vynálezu hydrogenuje dimetylénpropinol ZK 34506 v tetrahydrofuráne vodíkom na paládiu na uhlí. Hydrogenačný roztok sa potom podrobí zmene rozpúšťadla z tetrahydrofuránu na acetonitril. Acetor.itrilový roztok sa za použitia katalytického množstva chloridu ruténitého (1 % mol) a 3 ekvivalentov bromátu sodného cielene oxiduje pri teplote 40 °C až 60 °C na 5β-ΟΗ-DRSP. Veľkú nestabilitu δ-β-ΟΗ-DRSP voči kyselinám, Lewisovým kyselinám, ako sú napríklad zlúčeniny chrómu v starých prevádzkových spôsoboch, silným bázam alebo vysokým teplotám, ktorá je vo všetkých prípadoch odvodzovaná z vysokej hnacej sily pre väzbu termodynamicky stabilnejšieho delta-4,5-nenasýteného ketónu, sa podarí za zvolených reakčných podmienok selektívna syntéza 5^-OH-DRSP bez toho, že by saAnalogously to the methods known in the art, the process of the present invention hydrogenates dimethylene propinol ZK 34506 in tetrahydrofuran with hydrogen to palladium on carbon. The hydrogenation solution is then subjected to a solvent change from tetrahydrofuran to acetonitrile. The acetonitrile solution is specifically oxidized to 5β-ΟΗ-DRSP using a catalytic amount of ruthenium chloride (1 mol%) and 3 equivalents of sodium bromate at 40 ° C to 60 ° C. High instability of δ-β-DR-DRSP to acids, Lewis acids, such as chromium compounds in old process processes, strong bases or high temperatures, which in all cases derive from the high driving force for the coupling of the thermodynamically more stable delta-4,5 unsaturated ketone, under the selected reaction conditions, selective synthesis of 5-OH-DRSP is achieved without
31168/H pozorovala tvorba drospirenónu. 5-p-OH-DRSP sa môže izolovať z reakčnej zmesi jednoducho (aj prevádzkovo) uskutočniteľným zrážaním vodou.31168 / H observed drospirenone formation. 5-p-OH-DRSP can be isolated from the reaction mixture by simple (even operationally) precipitation with water.
Výťažky sú v rozmedzí 68 až 75 % cez obidva stupne, teda hydrogenáciu a nasledujúcu oxidáciu.The yields are in the range of 68 to 75% through both steps, i.e. hydrogenation and subsequent oxidation.
Z vlastných pokusov je známe, že drospirenón sa pri pôsobení kyseliny môže rozkladať dvoma reakčnými cestami. Za prvé sa drospirenón prevádza za kyslých podmienok ľahko na epimérny izolaktón ZK 35096It is known from our own experiments that drospirenone can be decomposed by two reaction pathways under the action of acid. First, drospirenone is readily converted under acidic conditions to the epimeric isolator ZK 35096
ZK 35096ZK 35096
Druhý vedľajší produkt vzniká pôsobením kyseliny chlorovodíkovej naThe second by - product is formed by the action of hydrochloric acid
6,7-metylénovú skupinu, čo vedie k produktu s otvoreným kruhom ZK 95673A 6,7-methylene group, resulting in an open ring product of ZK 95673
Obidva vedľajšie produkty sú za reakčných podmienok nového spôsobu tak ďaleko potlačené, že sú pozorované iba v množstve < 0,2 %.Both by-products are so far suppressed under the reaction conditions of the novel process that they are only observed in an amount of <0.2%.
Pri eliminácii sa dosiahne výťažok 96 % teórie. Celkový výťažok nového spôsobu je teda v rozmedzí 65 % až 72 % teórie.Elimination yielded 96% of theory. Thus, the total yield of the novel process is in the range of 65% to 72% of theory.
Ďalšia veľmi podstatná výhoda spôsobu podľa predloženého vynálezu v porovnaní so stavom techniky leží v oblasti ekológie. Podarilo sa toxickéAnother very substantial advantage of the process of the present invention over the prior art lies in the field of ecology. Toxic
31168/H zlúčeniny chrómu, ktoré boli doteraz používané na oxidáciu vo forme pyridíniumdichromátových soli a potom sa museli zneškodňovať vo forme svojich roztokov, nahradiť katalytickým množstvom kovu. Na to je možné zmes acetonitril-voda recyklovať azeotropickou destiláciou, takže taktiež tu nie je možné očakávať nebezpečenstvo pre životné prostredie.31168 / H chromium compounds which have hitherto been used for oxidation in the form of pyridinium dichromate salts and then had to be disposed of in the form of their solutions were replaced by a catalytic amount of metal. For this, the acetonitrile-water mixture can be recycled by azeotropic distillation, so that there is also no danger to the environment.
Ďalej sú predmetom predloženého vynálezu taktiež medziprodukty 7a(3-hydroxy-1-propyl)-6p,7p;15p,16p-dimetylén-5p-androstán-3p,5,17p-triol (ZK 92836) a 6p,7P;15p,16p-dimetylén-5p-hydroxy-3-oxo-17a-androstán-21,17karbolaktón (90965).Furthermore, the present invention also provides intermediates 7α (3-hydroxy-1-propyl) -6β, 7β; 15β, 16β-dimethylene-5β-androstane-3β, 5,17β-triol (ZK 92836) and 6β, 7β; 16β-dimethylene-5β-hydroxy-3-oxo-17α-androstane-21,17-carbolactone (90965).
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
6β, 7fi;15fi,16fi-dimetylén-5f3-hydroxy-3-oxo-17a-androstán-21,17-karbolaktón g 17a-(3-hydroxy-1-propinyl)-6p,7P;15p,16p-dimetylén-5p-androstán3β,5,17p-triolu sa v 1000 ml tetrahydrofuránu hydrogenuje za prítomnosti 10 g paládia na uhlí (10 %) a 3 ml pyridínu až sa spotrebujú 2 ekvivalenty vodíka. Potom sa katalyzátor odfiltruje a roztok sa zahustí do sucha, pričom sa získa 52,7 g 7a-(3-hydroxy-1-propyl)-6p,7p;15p,16p-dimetylén-5p-androstán-3p, 5,17p-triolu, ktorý sa bez ďalšieho čistenia nechá ďalej reagovať.6β, 7β, 15β, 16β-dimethylene-5β-hydroxy-3-oxo-17α-androstane-21,17-carbolactone g 17α- (3-hydroxy-1-propynyl) -6β, 7β; 15β, 16β-dimethylene- 5β-androstane-3β, 5,17β-triol is hydrogenated in 1000 mL of tetrahydrofuran in the presence of 10 g of palladium on carbon (10%) and 3 mL of pyridine until 2 equivalents of hydrogen are consumed. Then, the catalyst is filtered off and the solution is concentrated to dryness to give 52.7 g of 7α- (3-hydroxy-1-propyl) -6β, 7β; 15β, 16β-dimethylene-5β-androstane-3β, 5.17β-. triol, which is reacted further without further purification.
50,2 g 7a-(3-hydroxy-1-propyl)-6p,7p;15p,16p-dimetylén-5p-androstán3β,5,17p-triolu sa suspenduje v 250 ml acetonitrilu a zahreje sa na t eplotu 45°C. K tomu sa prikvapká 0,52 g chloridu ruténitého, rozpustených v 10 ml vody a 62,46 g bromátu sodného, rozpustených v 250 ml vody. Reakčná zmes sa mieša počas 2 hodín pri teplote 50 °C a roztok sa potom sekvencuje prídavkom 1000 ml vody. Ďalej sa pridá 200 ml etylesteru kyseliny octovej, fáza sa oddelí a potom sa vodná fáza extrahuje 600 ml etylesteru kyseliny octovej. Organické gázy sa spoja, vysušia sa pomocou bezvodého síranu sodného a zahustia sa do sucha. Pri tom sa získa 43,44 g 6p,7p;15p,16p-dimetylén-5phydroxy-3-oxo-17a-androstán-21,17-karbolaktónu ako surového produktu.50.2 g of 7α- (3-hydroxy-1-propyl) -6β, 7β, 15β, 16β-dimethylene-5β-androstane-3β, 5,17β-triol are suspended in 250 mL of acetonitrile and heated to 45 ° C. . 0.52 g of ruthenium chloride dissolved in 10 ml of water and 62.46 g of sodium bromate dissolved in 250 ml of water are added dropwise. The reaction mixture is stirred for 2 hours at 50 ° C and the solution is then sequenced by the addition of 1000 ml of water. Next, 200 ml of ethyl acetate are added, the phases are separated and then the aqueous phase is extracted with 600 ml of ethyl acetate. The organic gauze was combined, dried over anhydrous sodium sulfate and concentrated to dryness. 43.44 g of 6β, 7β, 15β, 16β-dimethylene-5-hydroxy-3-oxo-17α-androstane-21,17-carbolactone are obtained as a crude product.
31168/H31168 / H
Kryštalizáciou z acetón-izoéteru sa získa 6p,7p;15p,16p-dimetylén-5p-hydroxy3-oxo-17a-androstán-21,17-karbolaktón s teplotou topenia 216 až 218 °C. Hodnota otáčania dáva 65,6°.Crystallization from acetone-iso ether yielded 6β, 7β, 15β, 16β-dimethylene-5β-hydroxy-3-oxo-17α-androstane-21,17-carbolactone, m.p. 216-218 ° C. The rotation value gives 65.6 °.
(Natriumlínia, c = 1,02 v CHCI3).(Sodium lithium, c = 1.02 in CHCl 3 ).
Príklad 2Example 2
6β^;15β,16β-ά'ΜθΙγΙέη-3-οχο-17α-ρ^η-4-έη-21,17-Κ9Γ5οΐ8Μόη . PRír g 6p,7p; 15p,16p-dimetylén-5p-hydroxy-3-oxo-17a-androstán-21,17karbolaktónu sa suspenduje v 280 ml tetrahydrofuránu a potom sa zmieša s 10 % mólovými kyseliny p-toluénsulfónovej. Po 30 minútach sa pridá 125 ml nasýteného roztoku chloridu sodného a 8,2 ml 1 N roztoku hydroxidu sodného. Po oddelení fáz sa organická fáza vysuší pomocou bezvodého síranu sodného a zahustí sa do sucha, pričom sa získa 6p,7P;15p,16p-dimetylén-3-oxo-17apregn-4-én-21,17-karbolaktón ako surový produkt, ktorého čistota podľa HPLC je 93 %.6β ^; 15β, 16β-γ'ΜθΙγΙέη-3-οχο-17α-ρ ^ η-4-ηη-21,17-Κ9Γ5οΐ8Μόη. PR g 6p, 7p; The 15β, 16β-dimethylene-5β-hydroxy-3-oxo-17α-androstane-21,17-carbolactone was suspended in 280 mL of tetrahydrofuran and then mixed with 10% mole of p-toluenesulfonic acid. After 30 minutes, 125 mL of saturated sodium chloride solution and 8.2 mL of 1 N sodium hydroxide solution were added. After phase separation, the organic phase is dried over anhydrous sodium sulphate and concentrated to dryness to give 6β, 7β, 15β, 16β-dimethylene-3-oxo-17α-prep-4-ene-21,17-carbolactone as a crude product, HPLC purity 93%.
Ďalšie spracovanie sa môže uskutočňovať pomocou chromatografie.Further work-up can be carried out by chromatography.
Teplota topenia chromatografovanej látky je v rozmedzí 197,5 až 200 °C.Melting point: 197.5 - 200 ° C.
31168/H31168 / H
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| DE19633685A DE19633685C1 (en) | 1996-08-12 | 1996-08-12 | Production of drospirenone useful as steroidal agent |
| PCT/EP1997/004342 WO1998006738A1 (en) | 1996-08-12 | 1997-08-11 | Process for producing drospirenone and intermediates thereof |
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| Publication Number | Publication Date |
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| SK19499A3 true SK19499A3 (en) | 1999-10-08 |
| SK283546B6 SK283546B6 (en) | 2003-09-11 |
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| SK194-99A SK283546B6 (en) | 1996-08-12 | 1997-08-11 | Process for producing drospirenone and intermediates for its production |
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| EP (4) | EP2168974B1 (en) |
| JP (1) | JP3333524B2 (en) |
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| BR (1) | BR9711060A (en) |
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-
1996
- 1996-08-12 DE DE19633685A patent/DE19633685C1/en not_active Expired - Fee Related
-
1997
- 1997-08-11 TR TR1999/00262T patent/TR199900262T2/en unknown
- 1997-08-11 NZ NZ333697A patent/NZ333697A/en not_active IP Right Cessation
- 1997-08-11 PL PL97331530A patent/PL187474B1/en unknown
- 1997-08-11 DE DE59706887T patent/DE59706887D1/en not_active Expired - Lifetime
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| TC4A | Change of owner's name |
Owner name: BAYER PHARMA AKTIENGESELLSCHAFT, BERLIN, DE Effective date: 20111004 |
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| MG4A | Partial revocation of patent |
Effective date: 20121212 |
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| MK4A | Patent expired |
Expiry date: 20170811 |